Role of mTOR Complex 1 Signaling Pathway in the Pathogenesis of Diabetes Complications; A Mini Review

The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine-protein kinase that senses and combines various environmental signals to regulate the growth and homeostasis of human cells. This signaling pathway synchronizes many critical cellular processes and is involved in an increasing number of pathological conditions such as diabetes, cancer, obesity, and metabolic syndrome. Here, we review different complications of diabetes that are associated with mTOR complex 1 imbalance. We further discuss pharmacological approaches to treat diabetes complications linked to mTOR deregulation.

iabetes mellitus is a multifactorial disease characterized by high blood glucose concentration, and has become a significant health problem in developing countries (1,2). It has been associated with many human diseases such as cancers, cardiovascular, renal, and blood vessel failure (1,3,4). Marked high blood glucose (hyperglycemia) causes main symptoms of diabetes including polyuria, polydipsia, and polyphagia (1).
American diabetes association classifies diabetes mellitus in two different forms known as type 1 or insulin-dependent diabetes mellitus and type 2 or non-insulin-dependent diabetes mellitus (1).
Previous studies showed that the mammalian target of rapamycin (mTOR) signaling pathway has an essential role in the pathogenesis of metabolic syndrome, obesity, and diabetes (5). The mTOR is an evolutionarily well-conserved serine/threonineprotein kinase that serves as a critical regulator of cell metabolism, proliferation, growth, and survival (6)(7)(8)(9). Increased mTOR activity is common in most human diseases such as cancers, diabetes, and genetic disorders (5,10,11).

Role of mTORC1 in obesity
Obesity is a hazardous risk factor for the development of diabetes. Obesity may be observed with chronic systemic inflammation through excess fat tissue accumulation with necessary calorie exceeding energy saving (27). Hyperinsulinemia and insulin resistance are more common among obese patients and are related to a poor prognosis in diabetes (28). A growing body of evidence shows that the mTOR pathway is strongly involved in initiating and developing obesity and insulin resistance in metabolic syndrome (29,30). mTOR signaling pathway is crucial for adipogenesis, and Western diet (37)(38)(39)(40). These fundamental roles of mTORC1 in lipid metabolism make it a suitable target for reducing lipids synthesis during diabetes (41).

Role of mTORC1 in diabetic nephropathy
Diabetic nephropathy is a significant cause of end-stage kidney disease, and a major health   (51,52). Also, it has been shown that inflammation and oxidative stress have a significant role in diabetic retinopathy (53,54). In diabetic conditions, in the retina, advanced glycation end products (AGEs) generate oxidative stress, promote changes in proteins, and enhance the level of inflammatory cytokines that make changes to vascular function (55). A growing body of evidence implies that existing inflammatory processes within the retina make it more susceptible to the progression of diabetic retinopathy (56).

Relation between mTORC1, diabetes, and inflammation
Previous studies revealed the connection between inflammation and diabetes (57 However, it has been proved that a selective mTOR inhibitor is better than dual function inhibitors because of many different functions of diverse isoforms of PI3K (16,66). Two main mTOR inhibitors are sirolimus (rapamycin) and everolimus that have substantial inhibitory effects on the mTOR signaling pathway that may be beneficial in reducing diabetes complications. However, their use is restricted because of some adverse effects; therefore, it is necessary to do more studies about the clinical application of these drugs (67).

Conclusions and future perspectives
This review explained the significance of the